JP2010536838A - 酸含有脂質製剤 - Google Patents
酸含有脂質製剤 Download PDFInfo
- Publication number
- JP2010536838A JP2010536838A JP2010521479A JP2010521479A JP2010536838A JP 2010536838 A JP2010536838 A JP 2010536838A JP 2010521479 A JP2010521479 A JP 2010521479A JP 2010521479 A JP2010521479 A JP 2010521479A JP 2010536838 A JP2010536838 A JP 2010536838A
- Authority
- JP
- Japan
- Prior art keywords
- formulation
- glp
- acid
- fat
- active substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 title claims abstract description 93
- 150000002632 lipids Chemical class 0.000 title claims description 76
- 238000002360 preparation method Methods 0.000 title description 12
- 239000000203 mixture Substances 0.000 claims abstract description 305
- 238000009472 formulation Methods 0.000 claims abstract description 177
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 108
- 239000013543 active substance Substances 0.000 claims abstract description 84
- 239000011159 matrix material Substances 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 45
- 238000011282 treatment Methods 0.000 claims abstract description 35
- 239000003960 organic solvent Substances 0.000 claims abstract description 30
- 238000013268 sustained release Methods 0.000 claims abstract description 29
- 239000012730 sustained-release form Substances 0.000 claims abstract description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
- 239000001301 oxygen Substances 0.000 claims abstract description 27
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 claims description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 claims description 57
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 42
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 42
- 239000003814 drug Substances 0.000 claims description 26
- 239000004973 liquid crystal related substance Substances 0.000 claims description 26
- 238000001727 in vivo Methods 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 16
- 239000012530 fluid Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 10
- 150000003904 phospholipids Chemical class 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 8
- 150000001982 diacylglycerols Chemical class 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 229930003799 tocopherol Natural products 0.000 claims description 8
- 235000010384 tocopherol Nutrition 0.000 claims description 8
- 229960001295 tocopherol Drugs 0.000 claims description 8
- 239000011732 tocopherol Substances 0.000 claims description 8
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 8
- 239000002537 cosmetic Substances 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 206010033307 Overweight Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 100
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 75
- 102100040918 Pro-glucagon Human genes 0.000 description 75
- 239000002904 solvent Substances 0.000 description 49
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 description 36
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 description 36
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 32
- 150000007513 acids Chemical class 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 102000004196 processed proteins & peptides Human genes 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000003963 antioxidant agent Substances 0.000 description 19
- 235000006708 antioxidants Nutrition 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 108010011459 Exenatide Proteins 0.000 description 17
- 238000002347 injection Methods 0.000 description 17
- 239000007924 injection Substances 0.000 description 17
- 229960001519 exenatide Drugs 0.000 description 16
- 229940098779 methanesulfonic acid Drugs 0.000 description 16
- 235000000346 sugar Nutrition 0.000 description 16
- 230000015556 catabolic process Effects 0.000 description 15
- 238000006731 degradation reaction Methods 0.000 description 15
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 14
- -1 acylated sucrose ester Chemical class 0.000 description 12
- 230000008901 benefit Effects 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 11
- 239000002243 precursor Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000003860 storage Methods 0.000 description 11
- 239000003002 pH adjusting agent Substances 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 9
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 9
- 108010019598 Liraglutide Proteins 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 229960002701 liraglutide Drugs 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 7
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 7
- 230000003078 antioxidant effect Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- XVVOERDUTLJJHN-IAEQDCLQSA-N lixisenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 XVVOERDUTLJJHN-IAEQDCLQSA-N 0.000 description 7
- 108010004367 lixisenatide Proteins 0.000 description 7
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 7
- 230000000087 stabilizing effect Effects 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 210000001124 body fluid Anatomy 0.000 description 6
- 239000010839 body fluid Substances 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 6
- 108010063245 glucagon-like peptide 1 (7-36)amide Proteins 0.000 description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 238000010254 subcutaneous injection Methods 0.000 description 6
- 239000007929 subcutaneous injection Substances 0.000 description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 5
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 5
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000005642 Oleic acid Substances 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- 108010055448 CJC 1131 Proteins 0.000 description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 4
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 4
- 101000788682 Homo sapiens GATA-type zinc finger protein 1 Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 239000012867 bioactive agent Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000007857 degradation product Substances 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- AIWAEWBZDJARBJ-PXUUZXDZSA-N fz7co35x2s Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)CCN1C(C=CC1=O)=O)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 AIWAEWBZDJARBJ-PXUUZXDZSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 235000021313 oleic acid Nutrition 0.000 description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 235000019833 protease Nutrition 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108060003199 Glucagon Proteins 0.000 description 3
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 229960004308 acetylcysteine Drugs 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 238000011067 equilibration Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000001603 reducing effect Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 2
- PAZGBAOHGQRCBP-ZCXUNETKSA-N 1-Palmitoyl-2-oleoylglycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-ZCXUNETKSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108700001281 BIM 51077 Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000000604 cryogenic transmission electron microscopy Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000000859 incretin Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 230000009878 intermolecular interaction Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000003473 lipid group Chemical group 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000968 medical method and process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000010525 oxidative degradation reaction Methods 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- WRGVLTAWMNZWGT-VQSPYGJZSA-N taspoglutide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NC(C)(C)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 WRGVLTAWMNZWGT-VQSPYGJZSA-N 0.000 description 2
- 229950007151 taspoglutide Drugs 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- RLCKHJSFHOZMDR-UHFFFAOYSA-N (3R, 7R, 11R)-1-Phytanoid acid Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)=O RLCKHJSFHOZMDR-UHFFFAOYSA-N 0.000 description 1
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 1
- RLCKHJSFHOZMDR-PWCSWUJKSA-N 3,7R,11R,15-tetramethyl-hexadecanoic acid Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCC(C)CC(O)=O RLCKHJSFHOZMDR-PWCSWUJKSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XNLVWARRDCVUBL-UHFFFAOYSA-N 7-hexadecynoic acid Chemical compound CCCCCCCCC#CCCCCCC(O)=O XNLVWARRDCVUBL-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000003670 Carboxypeptidase B Human genes 0.000 description 1
- 108090000087 Carboxypeptidase B Proteins 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 102000000496 Carboxypeptidases A Human genes 0.000 description 1
- 108010080937 Carboxypeptidases A Proteins 0.000 description 1
- 108010059081 Cathepsin A Proteins 0.000 description 1
- 102000005572 Cathepsin A Human genes 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 102000000541 Defensins Human genes 0.000 description 1
- 108010002069 Defensins Proteins 0.000 description 1
- 101000761020 Dinoponera quadriceps Poneritoxin Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 1
- 102000006492 Histatins Human genes 0.000 description 1
- 108010019494 Histatins Proteins 0.000 description 1
- 101500028773 Homo sapiens Glucagon-like peptide 1(7-37) Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 108010018112 LY 315902 Proteins 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 235000021353 Lignoceric acid Nutrition 0.000 description 1
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229940122985 Peptide agonist Drugs 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical group O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 1
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 125000002714 alpha-linolenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 125000002886 arachidonoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229940084891 byetta Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- ZKALIGRYJXFMNS-XBDDSDALSA-N corticostatin Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(C)C)C(C)C)CC1=CC=CC=C1 ZKALIGRYJXFMNS-XBDDSDALSA-N 0.000 description 1
- 108010068597 corticostatin Proteins 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 150000001944 cysteine derivatives Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960002272 degarelix Drugs 0.000 description 1
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000003374 diacylglycerol group Chemical group 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000004626 essential fatty acids Nutrition 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229940074076 glycerol formal Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical group CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 235000021231 nutrient uptake Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940097156 peroxyl Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000003168 reconstitution method Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000029054 response to nutrient Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 1
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 1
- UVGUPMLLGBCFEJ-SWTLDUCYSA-N sucrose acetate isobutyrate Chemical compound CC(C)C(=O)O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@@H](COC(C)=O)O1 UVGUPMLLGBCFEJ-SWTLDUCYSA-N 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004954 trialkylamino group Chemical group 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Dispersion Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
【解決手段】本発明は、i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物を形成する組成物に関する。
本発明はさらに、とりわけ糖尿病の治療における、このような組成物の投与を含む治療方法、ならびに上記製剤を含有する充填済み投与装置およびキットに関する。
【選択図】なし
Description
未変性(ヒト)GLP−1(7−37):
His7−Ala−Glu−Gly10−Thr−Phe−Thr−Ser−Asp15−Val−Ser−Ser−Tyr−Leu20−Glu−Gly−Gln−Ala−Ala25−Lys−Glu−Phe−Ile−Ala30−Trp−Leu−Val−Lys−Gly−Arg−Gly37
未変性(ヒト):
GLP−1(7−36)アミド
ノボノルディスク(リラグルチド)
Arg34Lys26−(N−ε−(γ−Glu(N−α−ヘキサデカノイル)))−GLP−1(7−37)
コンジュケム(CJC−1131)
D−Ala8Lys37−(2−(2−(2−マレイミドプロピオンアミド(エトキシ)エトキシ)アセトアミド))−GLP−1(7−37)
サノフィ・アベンティス/ジーランド(AVE−010(ZP10)
His−Gly−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Leu−Ser−Lys−Gln−Met−Glu−Glu−Glu−Ala−Val−Arg−Leu−Phe−Ile−Glu−Trp−Leu−Lys−Asn−Gly−Gly−Pro−Ser−Ser−Gly−Ala−Pro−Pro−Ser−Lys−Lys−Lys−Lys−Lys−Lys
イーライリリー(エクセナチド)
His7−Gly−Glu−Gly10−Thr−Phe−Thr−Ser−Asp15−Leu−Ser−Lys−Gln−Met20−Glu−Glu−Glu−Ala−Val25−Arg−Leu−Phe−Ile−Glu30−Trp−Leu−Lys−Asn−Gly−Gly−Pro37−Ser−Ser−Gly−Ala−Pro−Pro−Pro−Ser−アミド
本明細書では「未変性のGLP−1」とは、ヒトGLP−1(7−37)および/またはヒトGLP−1(7−36)アミドを意味し、「リラグルチド」、「CJC−1131」、「AVE−010」、および「エクセナチド」なる語は上記の各活性物質を意味するために使用され、文脈上可能な場合はこれらの生理学的に許容される塩、エステル、および誘導体を包含する。未変性のGLP−1配列を含むこれらはすべて、本明細書では「GLP−1類似体」に包含される。他の適切なGLP−1類似体は、例えば、次の文献に記載されている。クヌーセン(Knudsen)ら、ジャーナル・オブ・メディシナルケミストリー(J. Med. Chem.)、2000年、43、1664〜1669;クヌーセン(Knudsen)、ジャーナル・オブ・メディシナルケミストリー(J. Med. Chem.)、2004年、47、4128〜4134;フイ(Hui)ら、ダイアベティス/メタボリズムリサーチ・アンド・リビューズ(Diabetes Metab. Res. Rev.)、2005年、21、313〜331;ならびにホルツ(Holz)およびチェパーニー(Chepurny)、カレントメディシナルケミストリー(Curr. Med. Chem.)、2003年、10、2471〜2483。これらの引用文献はその全体において参照により本書に援用され、特定の節が本明細書で言及されるが、これらの文書において言及されるGLP−1類似体の配列すべておよびGLP−1受容体アゴニストのすべてが本発明での使用に適している。本明細書で言及されるようなGLP−1受容体アゴニストは、上に記載されるようなおよび上に引用される文献のGLP−1類似体をすべて包含する。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質と、
iv)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤を提供する。
i)脂質をベースとする除放性マトリックスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)GLP−1受容体アゴニストなどの少なくとも1種のペプチド活性物質と、
iv)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤を提供する。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
d)GLP−1受容体アゴニストなどの少なくとも1種のペプチド活性物質と、
e)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤を提供し、
ここで当該前製剤は、水性流体との接触に際して、少なくとも1種の液晶相構造を形成するかまたは形成できる。
a)少なくとも1種のジアシルグリセロールと、
b)少なくとも1種のホスファチジルコリンと、
c)少なくとも1種の酸素含有有機溶媒と、
d)GLP−1受容体アゴニストなどの少なくとも1種のペプチド活性物質と、
e)少なくとも1種の脂溶性の酸と、の低粘度混合物を含むことになり、
ここで当該前製剤は、水性流体との接触に際して、少なくとも1種の液晶相構造を形成するかまたは形成できる。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤を非経口投与(例えば、筋肉内または好ましくは皮下)することを含む。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤をインビボで水性流体に曝露することを含む、デポー組成物の調製方法を提供する。
当該プロセスは、
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒、との低粘度混合物を形成すること、ならびに少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)を溶解または分散することを含み、GLP−1受容体アゴニストおよび少なくとも1種の脂溶性の酸は上記低粘度混合物に、または上記低粘度混合物を形成する前に成分i)もしくはii)の少なくとも一方に溶解または分散される。好ましくは、このように形成される非水性前製剤は、本明細書に記載の本発明の製剤であり、特に、成分i)は本明細書に記載の脂質マトリクス、とりわけ本明細書に示される成分a)およびb)を含む脂質マトリクスを含むことが好ましい。好ましくは、脂溶性の酸である成分は、ペプチド活性物質(例えば、GLP−1受容体アゴニスト)成分の添加前に加えられる。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、の低粘度混合物の使用を提供する。好ましくは、前製剤は本発明の好ましい態様に記載のとおりであり、例えば、
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
d)GLP−1受容体アゴニストなどの少なくとも1種のペプチド活性物質と、
e)少なくとも1種の脂溶性の酸と、の低粘度混合物であってもよく、
ここで当該前製剤は、水性流体との接触に際して、少なくとも1種の液晶相構造を形成できる。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
d)少なくとも1種のGLP−1受容体アゴニストと、
e)少なくとも1種の脂溶性の酸と、の低粘度混合物を含む非水性前製剤を上記対象者に投与することを含む。
a)少なくとも1種の中性ジアシル脂質および/またはトコフェロール、
b)少なくとも1種のリン脂質、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒、
d)少なくとも1種のGLP−1受容体アゴニスト、および
e)少なくとも1種の脂溶性の酸、の
I型糖尿病、II型糖尿病、過剰体重、および/または肥満の治療用デポーのインビボ形成に用いる低粘度前製剤薬剤の製造での使用を提供する。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)上記少なくとも1種のペプチド活性物質と、
iv)上記少なくとも1種の脂溶性の酸と、の低粘度混合物を含む。
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)上記少なくとも1種のペプチド活性剤と、
iv)上記少なくとも1種の脂溶性の酸と、の低粘度混合物として調合することを含む。
a)少なくとも1種のジアシルグリセロールおよび/または少なくとも1種のトコフェロール、
b)少なくとも1種のホスファチジルコリン。
i)本明細書に記載の成分i)およびii)(好ましくはa)〜c))の低粘度混合物を含有する第1の容器と、
ii)少なくとも1種のペプチド活性物質(好ましくは少なくとも1種のGLP−1受容体アゴニスト)を含有する第2の容器と、
iii)任意に第3の容器中、好ましくは第2の容器中、最も好ましくは第1の容器中にある脂溶性の酸と、
iv)任意に、かつ好ましくは、下記のものの少なくとも1つ:
1)少なくとも1つの注射器(上記第1および第2の容器の片方または両方であってもよい)、
2)本明細書に記載のものなどの投与用針、
3)第1および第2の容器の内容物から本発明の組成物を生成させることに関する説明書、
4)本明細書に記載のデポーを形成するための、投与に関する説明書、とを含む2部構成のキットを提供する。
実施例
ホスファチジルコリン(PC)(「SPC」、リポイドS100)とジオレイン酸グリセロール(GDO)とを異なる割合で含み、エタノール(EtOH)を溶媒として含む注射製剤を調製し、デポー前駆体製剤を過剰量の水で平衡化した後、各種液晶相が得られることを例証した。
約25%のEtOHを有するPC/GDO/EtOHの混合物を、実施例1の方法に従って製造した。回転蒸発器(真空、40℃で1時間、続いて50℃で2時間)を用いて混合物からEtOHを完全またはほぼ完全に除去し、得られた混合物をガラスバイアルで計量した後、1、3、5、10、または20%の溶媒(EtOH、プロピレングリコール(PG)、またはn−メチルピロリドン(NMP))を加えた。試料を数日間平衡化させた後、自動間隔設定(automatic gap setting)を備えるキャリメド(CarriMed)CSL100レオメータを用いて粘度を測定した。
様々な容量(1、2、および6ml/kg)のデポー前駆体(36重量%PC、54重量%GDO、および10重量%EtOH)をラットに注射し、14日後に再び除去した。この期間後でもラットの皮下には相当な量の製剤がなお存在することが分かった。表3を参照のこと。
実施例4〜8で使用したGLP−1物質および賦形剤を下記表に示す。
実施例4〜8で使用したGLP−1物質および賦形剤
SPC、GDO、EtOH、PG、およびMeSulf(シグマ・アルドリッチ社、スウェーデン)を含む脂質製剤を実施例4に記載のように調製した。次のような脂質組成であった。SPC/GDO/EtOH/PG/MeSulf=43.2/43.2/3.0/10.0/0.5重量%。
SPC、GDO、EtOH、PG、およびEtOH・HCl(EtOH中1.25M HCl、スウェーデンのフルカ社より)を含む脂質製剤を実施例4に記載のように調製した。次のような脂質組成であった。SPC/GDO/PG/EtOH・HCl=43.0/43.0/10.0/4.0重量%。
SPC、GDO、P80(クローダ社、米国)、EtOH、PG、およびMeSulfを含む脂質製剤を実施例4に記載のように調製した。次のような脂質組成であった。SPC/GDO/P80/EtOH/PG/MeSulf=41.0/41.0/5.0/3.0/10.0/0.5重量%。
MeSulfを含む脂質製剤を実施例4に記載のように調製した。必要量のGLP−1(Ac)粉末を6mLガラスバイアルで計量し、次いで3重量%のGLP−1(0)の名目上の薬物含有量を達成するのに適当な量の脂質製剤を加えた。試料を手短にボルテックスさせ、次いで完全に均一で透明な試料が得られるまで室温で継続的に転倒混和させた(1〜3日)。試料の名目上の組成を下記表に示す。
Claims (21)
- i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む非水性前製剤。 - i)脂質をベースとする除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む、請求項1に記載の非水性前製剤。 - a)少なくとも1種の中性ジアシル脂質および/またはトコフェロールと、
b)少なくとも1種のリン脂質と、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
d)少なくとも1種のペプチド活性物質と、
e)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む、請求項1または2に記載の非水性前製剤であって、
前記前製剤は、水性流体との接触に際して、少なくとも1種の液晶相構造を形成するかまたは形成できる、非水性前製剤。 - a)少なくとも1種のジアシルグリセロールと、
b)少なくとも1種のホスファチジルコリンと、
c)少なくとも1種の酸素含有有機溶媒と、
d)少なくとも1種のペプチド活性物質と、
e)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む、請求項1〜3のいずれかに記載の非水性前製剤であって、
前記前製剤は、水性流体との接触に際して、少なくとも1種の液晶相構造を形成するかまたは形成できる、非水性前製剤。 - 前記ペプチド活性物質がGLP−1受容体アゴニストである、請求項1〜4のいずれかに記載の非水性前製剤。
- 成分a)が30〜70重量%の割合で存在する、請求項3〜5に記載の非水性前製剤。
- 成分b)が30〜60重量%の割合で存在する、請求項3〜6に記載の非水性前製剤。
- 前記有機溶媒が0.1〜20重量%の割合で存在する、請求項1〜7に記載の非水性前製剤。
- 前記有機溶媒がエタノールおよび任意にプロピレングリコールを含む、請求項1〜7に記載の非水性前製剤。
- ヒトまたはヒト以外の動物(好ましくは哺乳類)の身体へのペプチド活性物質(とりわけGLP−1受容体アゴニスト)の送達方法であって、
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む非水性前製剤を非経口投与することを含む方法。 - 前記非水性前製剤が請求項1〜9のいずれかに記載のものである、請求項10に記載の方法。
- i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物を含む非水性前製剤をインビボで水性流体に曝露することを含む、デポー組成物の調製方法。 - 対象者(好ましくは哺乳類)へのペプチド生物活性物質の投与に適した非水性前製剤の形成プロセスであって、
i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒との低粘度混合物を形成すること、ならびに
少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と少なくとも1種の脂溶性の酸とを前記低粘度混合物に、または前記低粘度混合物を形成する前に成分i)もしくはii)の少なくとも一方に、溶解または分散させることを含む、プロセス。 - i)非高分子の除放性マトリクスと、
ii)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒と、
iii)少なくとも1種のペプチド活性物質(好ましくはGLP−1受容体アゴニスト)と、
iv)少なくとも1種の脂溶性の酸と、
の低粘度混合物の使用であって、
前記ペプチド活性物質の持続投与に用いる非水性前製剤の製造における使用。 - 前記低粘度混合物が請求項1〜9のいずれか一項に記載のものである、請求項14に記載の使用。
- ヒトまたはヒト以外の哺乳類対象者の治療方法であって、
前記対象者に請求項1〜9のいずれかに記載の非水性前製剤を投与することを含む方法。 - 糖尿病、I型糖尿病、II型糖尿病、過剰体重、および肥満から選ばれる少なくとも1つの症状に対処するための、治療を必要とするヒトまたはヒト以外の哺乳類対象者の治療のための請求項16に記載の方法であって、
前記前製剤がGLP−1受容体アゴニストを含む方法。 - ヒトまたはヒト以外の哺乳類対象者の美容的な処置方法であって、
前記対象者に請求項1〜9のいずれかに記載の非水性前製剤を投与することを含む方法。 - a)少なくとも1種の中性ジアシル脂質および/またはトコフェロール、
b)少なくとも1種のリン脂質、
c)少なくとも1種の生体適合性の(好ましくは酸素を含有する)有機溶媒、
d)少なくとも1種のGLP−1受容体アゴニスト、ならびに
e)少なくとも1種の脂溶性の酸、の
I型糖尿病、II型糖尿病、過剰体重、および/または肥満の治療用デポーのインビボ形成に用いる低粘度前製剤薬剤の製造での使用。 - 請求項1〜9のいずれかに記載の前製剤を含む充填済み投与装置。
- 請求項20に記載の投与装置を含むキット。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0716385.0 | 2007-08-22 | ||
GBGB0716385.0A GB0716385D0 (en) | 2007-08-22 | 2007-08-22 | Formulations |
PCT/GB2008/002857 WO2009024795A1 (en) | 2007-08-22 | 2008-08-22 | Acid containing lipid formulations |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015157619A Division JP6411299B2 (ja) | 2007-08-22 | 2015-08-07 | 酸含有脂質製剤 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2010536838A true JP2010536838A (ja) | 2010-12-02 |
JP2010536838A5 JP2010536838A5 (ja) | 2011-09-29 |
JP5851096B2 JP5851096B2 (ja) | 2016-02-03 |
Family
ID=38599087
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010521479A Active JP5851096B2 (ja) | 2007-08-22 | 2008-08-22 | 酸含有脂質製剤 |
JP2015157619A Active JP6411299B2 (ja) | 2007-08-22 | 2015-08-07 | 酸含有脂質製剤 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015157619A Active JP6411299B2 (ja) | 2007-08-22 | 2015-08-07 | 酸含有脂質製剤 |
Country Status (12)
Country | Link |
---|---|
US (2) | US9820934B2 (ja) |
EP (1) | EP2194969B1 (ja) |
JP (2) | JP5851096B2 (ja) |
KR (2) | KR20100061493A (ja) |
CN (2) | CN101861140A (ja) |
CA (1) | CA2697034C (ja) |
DK (1) | DK2194969T3 (ja) |
ES (1) | ES2708854T3 (ja) |
GB (1) | GB0716385D0 (ja) |
HK (1) | HK1217440A1 (ja) |
SI (1) | SI2194969T1 (ja) |
WO (2) | WO2009024797A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016006097A (ja) * | 2007-08-22 | 2016-01-14 | カムルス エービー | 酸含有脂質製剤 |
WO2020202926A1 (ja) | 2019-03-29 | 2020-10-08 | 富士フイルム株式会社 | 生体材料 |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9649382B2 (en) | 2005-01-14 | 2017-05-16 | Camurus Ab | Topical bioadhesive formulations |
US8920782B2 (en) | 2005-01-14 | 2014-12-30 | Camurus Ab | Topical bioadhesive formulations |
US8871712B2 (en) * | 2005-01-14 | 2014-10-28 | Camurus Ab | Somatostatin analogue formulations |
CA2595385C (en) | 2005-01-21 | 2011-01-25 | Camurus Ab | Pharmaceutical lipid compositions |
WO2006131730A1 (en) | 2005-06-06 | 2006-12-14 | Camurus Ab | Glp-1 analogue formulations |
GB0711656D0 (en) | 2007-06-15 | 2007-07-25 | Camurus Ab | Formulations |
GB0815435D0 (en) | 2008-08-22 | 2008-10-01 | Camurus Ab | Formulations |
EP2359843A1 (en) * | 2010-01-21 | 2011-08-24 | Sanofi | Pharmaceutical composition for treating a metabolic syndrome |
WO2012160212A1 (en) * | 2011-05-25 | 2012-11-29 | Camurus Ab | Peptide controlled-release formulations |
BR112013030104A8 (pt) * | 2011-05-25 | 2021-09-08 | Camurus Ab | Pré-formulação, processo para a formação de uma pré-formulação, método de tratamento cosmético, dispositivo de administração preenchido, e, kit |
JP2014520159A (ja) * | 2011-06-24 | 2014-08-21 | アミリン・ファーマシューティカルズ,リミテッド・ライアビリティ・カンパニー | Glp−1受容体アゴニストの徐放性製剤による糖尿病の治療方法 |
KR101494594B1 (ko) | 2011-08-30 | 2015-02-23 | 주식회사 종근당 | 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
EP2787975B1 (en) * | 2011-12-05 | 2017-10-04 | Camurus AB | Robust controlled-release formulations |
AU2013265210B2 (en) | 2012-05-25 | 2016-09-15 | Camurus Ab | Somatostatin receptor agonist formulations |
KR101586789B1 (ko) | 2012-12-28 | 2016-01-19 | 주식회사 종근당 | 양이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
KR101586791B1 (ko) | 2012-12-28 | 2016-01-19 | 주식회사 종근당 | GnRH 유도체의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
KR101586790B1 (ko) * | 2012-12-28 | 2016-01-19 | 주식회사 종근당 | 음이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물 |
CA2995392C (en) * | 2015-09-04 | 2023-08-15 | Hailiang Chen | Stabilized glucagon solutions |
EP3888667B1 (en) * | 2016-06-09 | 2023-10-25 | AmideBio LLC | Glucagon analog and methods of use thereof |
RU2020119425A (ru) * | 2017-11-15 | 2021-12-15 | Ритм Фармасьютикалз, Инк. | Составы на основе пептидов с длительным высвобождением |
CN114144170B (zh) | 2019-05-31 | 2024-04-05 | Xeris药物公司 | 非质子极性溶剂中的稳定治疗组合物及其制造方法 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08505367A (ja) * | 1992-10-16 | 1996-06-11 | スミスクライン・ビーチャム・コーポレイション | 医薬用エマルジョン組成物 |
JP2003503339A (ja) * | 1999-06-24 | 2003-01-28 | アボット・ラボラトリーズ | 抗癌剤を含有する自己乳化システム |
WO2005046642A1 (en) * | 2003-11-07 | 2005-05-26 | Camurus Ab | Compositions of lipids and cationic peptides |
WO2005117830A1 (en) * | 2004-06-04 | 2005-12-15 | Camurus Ab | Liquid depot formulations |
WO2006077362A1 (en) * | 2005-01-21 | 2006-07-27 | Camurus Ab | Pharmaceutical lipid compositions |
WO2006131730A1 (en) * | 2005-06-06 | 2006-12-14 | Camurus Ab | Glp-1 analogue formulations |
JP2007504124A (ja) * | 2003-08-29 | 2007-03-01 | ノバガリ、ファルマ、エスアー | 難水溶性薬剤の投与のための自己ナノ乳化油性製剤 |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
GB2209937B (en) | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US5340802A (en) | 1989-06-30 | 1994-08-23 | Abbott Laboratories | Peptide analog type-B CCK receptor ligands |
PH30995A (en) | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
MY107937A (en) | 1990-02-13 | 1996-06-29 | Takeda Chemical Industries Ltd | Prolonged release microcapsules. |
WO1993006921A1 (en) | 1991-10-04 | 1993-04-15 | Gs Biochem Ab | Particles, method of preparing said particles and uses thereof |
DE69229640T2 (de) | 1991-10-04 | 1999-12-16 | Gs Development Ab, Malmoe | Teilchen, methode zur herstellung der teilchen und deren verwendung |
US6228383B1 (en) | 1994-03-03 | 2001-05-08 | Gs Development Ab | Use of fatty acid esters as bioadhesive substances |
WO1995026715A2 (en) | 1994-03-30 | 1995-10-12 | Dumex-Alpharma A/S | Use of fatty acid esters as bioadhesive substances |
SE518578C2 (sv) | 1994-06-15 | 2002-10-29 | Gs Dev Ab | Lipidbaserad komposition |
FR2725369B1 (fr) | 1994-10-07 | 1997-01-03 | Oreal | Composition cosmetique ou dermatologique constituee d'une emulsion huile dans eau a base de globules huileux pourvus d'un enrobage cristal liquide lamellaire |
EP0871489A1 (en) | 1995-10-12 | 1998-10-21 | Gs Development Ab | A pharmaceutical composition for administration of an active substance to or through a skin or mucosal surface |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
ATE272394T1 (de) | 1996-10-31 | 2004-08-15 | Takeda Chemical Industries Ltd | Zubereitung mit verzögerter freisetzung |
JP2001524958A (ja) | 1997-04-17 | 2001-12-04 | ジーエス ディベロップメント アクティエボラーグ | 新規な液晶をベースとする生物接着性薬剤送出系 |
US6638621B2 (en) | 2000-08-16 | 2003-10-28 | Lyotropic Therapeutics, Inc. | Coated particles, methods of making and using |
US20040018241A1 (en) | 1997-09-26 | 2004-01-29 | Noven Pharmaceuticals, Inc. | Bioadhesive compositions and methods for topical administration of active agents |
US6320017B1 (en) | 1997-12-23 | 2001-11-20 | Inex Pharmaceuticals Corp. | Polyamide oligomers |
JP4072319B2 (ja) * | 1998-03-13 | 2008-04-09 | ノヴォ ノルディスク アクティーゼルスカブ | 安定化水溶性ペプチド溶液 |
BE1011899A6 (fr) | 1998-04-30 | 2000-02-01 | Ucb Sa | Compositions pharmaceutiques gelifiables utilisables. |
SI1140148T1 (sl) | 1998-12-22 | 2006-04-30 | Lilly Co Eli | Stabilna formulacija raztopine glukagonu podobnega peptida-1 |
US20020153508A1 (en) | 2000-06-29 | 2002-10-24 | Lynch Matthew Lawrence | Cubic liquid crystalline compositions and methods for their preparation |
DE60129156T2 (de) * | 2000-11-29 | 2008-03-13 | Lyotropic Therapeutics, Inc. | Lösungsmittelsysteme für pharmazeutische mittel |
US7008646B2 (en) | 2001-02-20 | 2006-03-07 | Patrick Thomas Spicer | Cubic liquid crystalline compositions and methods for their preparation |
US6936187B2 (en) | 2001-02-21 | 2005-08-30 | Matthew Lawrence Lynch | Functionalized cubic liquid crystalline phase materials and methods for their preparation and use |
US6656385B2 (en) | 2001-02-21 | 2003-12-02 | The Procter & Gamble Company | Functionalized cubic liquid crystalline phase materials and methods for their preparation and use |
US6991809B2 (en) | 2001-06-23 | 2006-01-31 | Lyotropic Therapeutics, Inc. | Particles with improved solubilization capacity |
DK1412384T3 (da) | 2001-06-28 | 2008-04-28 | Novo Nordisk As | Stabil formulering af modificeret GLP-1 |
WO2003057235A2 (en) | 2002-01-10 | 2003-07-17 | Imperial College Innovations Ltd | Modification of feeding behavior |
US7622118B2 (en) | 2002-07-15 | 2009-11-24 | Board Of Regents, The University Of Texas System | Cancer treatment methods using selected antibodies to aminophospholipids |
US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
GB0305941D0 (en) | 2003-03-14 | 2003-04-23 | Camurus Ab | Composition |
GB0307777D0 (en) | 2003-04-04 | 2003-05-07 | Medical Res Council | Conjugate compounds |
JP5180474B2 (ja) | 2003-08-04 | 2013-04-10 | カムルス エービー | 両親媒性粒子の特性を改良する方法 |
JP5518282B2 (ja) | 2003-09-01 | 2014-06-11 | ノヴォ ノルディスク アー/エス | 安定なペプチドの製剤 |
GB0322033D0 (en) | 2003-09-19 | 2003-10-22 | Camurus Ab | Composition |
WO2005063213A1 (en) | 2003-12-19 | 2005-07-14 | Biodelivery Sciences International, Inc. | Rigid liposomal cochleate and methods of use and manufacture |
CA2554052C (en) | 2004-01-23 | 2013-10-22 | Camurus Ab | Ternary non-lamellar lipid compositions of structure forming amphiphile, structure swelling amphiphile and dispersion stabilising amphiphile |
GB0401513D0 (en) | 2004-01-23 | 2004-02-25 | Camurus Ab | Compositions |
JP5513713B2 (ja) | 2004-08-04 | 2014-06-04 | カムルス エービー | 非層状分散を生じる組成物 |
PL1848403T3 (pl) * | 2005-01-14 | 2010-09-30 | Camurus Ab | Preparaty bioadhezyjne o działaniu miejscowym |
US8871712B2 (en) | 2005-01-14 | 2014-10-28 | Camurus Ab | Somatostatin analogue formulations |
US8920782B2 (en) | 2005-01-14 | 2014-12-30 | Camurus Ab | Topical bioadhesive formulations |
CA2594711C (en) | 2005-01-14 | 2012-11-06 | Camurus Ab | Somatostatin analogue formulations |
EP1948271B1 (en) | 2005-11-17 | 2013-10-02 | Zogenix, Inc. | Delivery of viscous formulations by needle-free injection |
GB0711656D0 (en) | 2007-06-15 | 2007-07-25 | Camurus Ab | Formulations |
GB0716385D0 (en) * | 2007-08-22 | 2007-10-03 | Camurus Ab | Formulations |
GB0815435D0 (en) | 2008-08-22 | 2008-10-01 | Camurus Ab | Formulations |
-
2007
- 2007-08-22 GB GBGB0716385.0A patent/GB0716385D0/en not_active Ceased
-
2008
- 2008-08-22 US US12/674,226 patent/US9820934B2/en active Active
- 2008-08-22 KR KR1020107005870A patent/KR20100061493A/ko active Search and Examination
- 2008-08-22 CN CN200880112354A patent/CN101861140A/zh active Pending
- 2008-08-22 CN CN201510450621.4A patent/CN105055303A/zh active Pending
- 2008-08-22 SI SI200832033T patent/SI2194969T1/sl unknown
- 2008-08-22 DK DK08788417.7T patent/DK2194969T3/en active
- 2008-08-22 WO PCT/GB2008/002863 patent/WO2009024797A1/en active Application Filing
- 2008-08-22 ES ES08788417T patent/ES2708854T3/es active Active
- 2008-08-22 WO PCT/GB2008/002857 patent/WO2009024795A1/en active Application Filing
- 2008-08-22 EP EP08788417.7A patent/EP2194969B1/en active Active
- 2008-08-22 CA CA2697034A patent/CA2697034C/en active Active
- 2008-08-22 KR KR1020157035380A patent/KR20160067063A/ko not_active Application Discontinuation
- 2008-08-22 JP JP2010521479A patent/JP5851096B2/ja active Active
-
2015
- 2015-08-07 JP JP2015157619A patent/JP6411299B2/ja active Active
-
2016
- 2016-05-13 HK HK16105476.4A patent/HK1217440A1/zh unknown
-
2017
- 2017-10-26 US US15/794,537 patent/US20180207089A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08505367A (ja) * | 1992-10-16 | 1996-06-11 | スミスクライン・ビーチャム・コーポレイション | 医薬用エマルジョン組成物 |
JP2003503339A (ja) * | 1999-06-24 | 2003-01-28 | アボット・ラボラトリーズ | 抗癌剤を含有する自己乳化システム |
JP2007504124A (ja) * | 2003-08-29 | 2007-03-01 | ノバガリ、ファルマ、エスアー | 難水溶性薬剤の投与のための自己ナノ乳化油性製剤 |
WO2005046642A1 (en) * | 2003-11-07 | 2005-05-26 | Camurus Ab | Compositions of lipids and cationic peptides |
WO2005117830A1 (en) * | 2004-06-04 | 2005-12-15 | Camurus Ab | Liquid depot formulations |
WO2006077362A1 (en) * | 2005-01-21 | 2006-07-27 | Camurus Ab | Pharmaceutical lipid compositions |
WO2006131730A1 (en) * | 2005-06-06 | 2006-12-14 | Camurus Ab | Glp-1 analogue formulations |
Non-Patent Citations (2)
Title |
---|
HONG,J. ET AL, JOURNAL OF CONTROLLED RELEASE, vol. 110, no. 2, JPN6013003698, 2006, pages 332 - 8, ISSN: 0002442644 * |
医薬品添加物事典 2007, vol. 第1版, JPN6014006012, 25 July 2007 (2007-07-25), pages 21 - 2, ISSN: 0002745594 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016006097A (ja) * | 2007-08-22 | 2016-01-14 | カムルス エービー | 酸含有脂質製剤 |
WO2020202926A1 (ja) | 2019-03-29 | 2020-10-08 | 富士フイルム株式会社 | 生体材料 |
Also Published As
Publication number | Publication date |
---|---|
CN101861140A (zh) | 2010-10-13 |
US20180207089A1 (en) | 2018-07-26 |
WO2009024795A1 (en) | 2009-02-26 |
JP5851096B2 (ja) | 2016-02-03 |
CA2697034C (en) | 2016-09-27 |
US9820934B2 (en) | 2017-11-21 |
KR20100061493A (ko) | 2010-06-07 |
HK1217440A1 (zh) | 2017-01-13 |
SI2194969T1 (sl) | 2019-04-30 |
ES2708854T3 (es) | 2019-04-11 |
KR20160067063A (ko) | 2016-06-13 |
GB0716385D0 (en) | 2007-10-03 |
US20120028890A1 (en) | 2012-02-02 |
CN105055303A (zh) | 2015-11-18 |
JP6411299B2 (ja) | 2018-10-24 |
JP2016006097A (ja) | 2016-01-14 |
WO2009024797A1 (en) | 2009-02-26 |
EP2194969A1 (en) | 2010-06-16 |
CA2697034A1 (en) | 2009-02-26 |
DK2194969T3 (en) | 2019-02-11 |
EP2194969B1 (en) | 2018-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6411299B2 (ja) | 酸含有脂質製剤 | |
JP5198261B2 (ja) | Glp−1類似体製剤 | |
JP6415673B2 (ja) | 制御放出ペプチド製剤 | |
EP1843746B1 (en) | Somatostatin analogue formulations | |
KR20100023033A (ko) | 펩티드 서방형 제형 | |
AU2012260821A1 (en) | Controlled release peptide formulations | |
JP6374380B2 (ja) | ソマトスタチン受容体作動薬製剤 | |
NZ617828B2 (en) | Controlled release peptide formulations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110815 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110815 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130129 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130422 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130430 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130520 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130527 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130621 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130628 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130729 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140213 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140502 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140513 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140604 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140611 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140703 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140710 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140916 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20141210 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20141217 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150107 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150209 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150316 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20150407 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150807 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150915 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20151009 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20151117 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20151202 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5851096 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |